This invention relates to a series of indole, indazole and benzimidazole derivatives, which are antithrombotic agents, having utility in a variety of therapeutic areas including the prevention and/or treatment of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilisation trauma, application of lower limb plaster casts, or fractures of the lower limbs or pelvis; recurrent DVT; DVT during pregnancy when there is a previous history thereof; reocclusion following thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; transient ischaemic attacks; disseminated intravascular coagulation; coagulation in extra-corporeal circuits; occlusion of arterio-venous shunts and blood vessel grafts (including coronary artery by-pass grafts); and restenosis and occlusion following angioplasty. They also have utility as an adjunct to thrombolytic therapy.
The compounds of the invention are potent and selective inhibitors of thrombin, which is the final serine protease enzyme in the coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to produce fibrin which forms linear insoluble polymers which, in turn, are cross-linked by factor XIIIa, itself activated by thrombin. In addition, thrombin regulates its own production by activation of factors V and VIII earlier in the cascade. It also has important actions at the cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation. Thus thrombin has a central regulatory role in haemostasis and thrombus formation.
Clearly then, potent, selective and orally bioavailable thrombin inhibitors represent an attractive target for the convenient therapeutic control of thrombosis. In addition, thrombin potently causes neurite retraction and therefore a thrombin inhibitor is of potential therapeutic utility in the treatment of acute and chronic neurodegenerative disorders. Furthermore, the compounds disclosed herein are of potential value in the treatment of inflammatory disorders and scarring, and in wound healing.
Because of their potential as substrate mimics, arginine derivatives have been explored as thrombin inhibitors and this work led to the discovery of argatroban (see Cardiovascular Drug Rev., 1991, 9, 247). In turn, other research groups have sought to express the basic arginine function in alternative structures; for example, WO-A-95/13274 discloses amidinophenylalanine and amidinopyridylalanine derivatives as antithrombotic agents. Further variations on the theme of arginine mimicry amongst thrombin inhibitors are represented by, inter alia, the guanidinyl- and amidinyl-substituted heterocyclic compounds disclosed in EP-A-0623595. In general, however, compounds containing the basic arginine, amidine or guanidine function have poor oral bioavailability and are poorly selective since they inhibit trypsin as well as thrombin.
Thrombin inhibitors containing a 3-amino-2-pyridone acetamide template have been disclosed by Corvas Int Inc in PCT patent reference WO 96/18644 and COR Therapeutics Inc in WO 98/16547. Compounds of the type disclosed within WO 96/18644 and WO 98/16547 contain a guanidino function as an arginine mimic and are likely to be irreversible inhibitors of thrombin by virtue of the presence of an aldehyde or an activated carbonyl fragment.
Thrombin inhibitors containing a 3-amino-2-pyridone or pyrazinone acetamide fragment and an arginine mimic which is not a guanidine or amidine have been disclosed by Merck in PCT patent reference WO 97/40024, WO 97/01338, WO 97/30708, WO 98/09987, WO 99/11267 and in Bioorg Med Cher) Letters. 1997, 7, p1497; 1998, 8, p1719, 1998, 8, p817.
The present inventors have now found a class of non basic or weakly basic bicyclic heterocyclic arginine mimics which are highly potent, selective, reversible thrombin inhibitors with good oral bioavailability.
Accordingly, the present invention provides compound of formula (I): 
wherein:
R1 is hydrogen, C1-C4 alkyl, perfluoro C1-C4 alkyl, OC1-C4 alkyl, fluoro or chloro;
R2 is hydrogen, CH3, or CF3;
R3 is hydrogen, C1-C4 alkyl, perfluoro C1-C4 alkyl, OC1-C4 alkyl, fluoro or chloro;
R4 is hydrogen or C1-C4 alkyl;
R5 is hydrogen or C1-C4 alkyl;
R6 is hydrogen, fluoro or chloro;
C1-C6 alkyl, C3-C6 carbocyclic (eg cyclopropyl), C3-C6 carbocyclicC1-C4 alkyl wherein the alkyl and carbocyclic may optionally be substiututed by C1-C4 alkyl or fluoro (eg perfluoro C1-C4 alkyl), and wherein the carbocycle contains zero, one or more double bonds;
or R5 and R6 together form a bridging chain containing 2 or 3 carbon atoms;
Y is hydrogen, chloro, fluoro, bromo, methyl or CF3;
W and X are independently CH, CF, CCl or N;
V is C or N;
Bxe2x80x94Axe2x80x94 is any one of the following fragments:
Bxe2x80x94C(R8)(R9)xe2x80x94
Bxe2x80x94CH2xe2x80x94C(R8)(R9)xe2x80x94
Bxe2x80x94C(R8)(R9)xe2x80x94CH2xe2x80x94
Bxe2x80x94CH2xe2x80x94C(R8)(R9)xe2x80x94CH2xe2x80x94
Bxe2x80x94C(R8)(R9)xe2x80x94CH2xe2x80x94CH2xe2x80x94
Bxe2x80x94CH2xe2x80x94CH2xe2x80x94C(R8)(R9)xe2x80x94
wherein:
R8 and R9 are independently hydrogen, xe2x80x94(CH2)mN(R10)(R11), xe2x80x94CH2Oxe2x80x94(CH2)2N(R10)(R11), or R8 and R9 together form a 4 to 6 membered ring containing a nitrogen atom present as N(R12); and
m is 0,1 and 2 (preferably m=1) except where A represents xe2x80x94C(R8)(R9)xe2x80x94 when m is 1 or 2;
R10 and R11 are independently selected from hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain;
or R10 and R11 together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated heterocyclic ring wherein when the ring is six membered it may optionally contain one oxygen atom or a nitrogen atom present as N(R12);
R12 is hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain;
B is phenyl or a 5 to 6 membered aromatic heterocyclic ring containing up to two heteroatoms independently selected from oxygen, sulphur and nitrogen;
R7 (when B is phenyl or an aromatic heterocycle) is one or more of hydrogen, C1-C6 alkyl, perfluoro C1-C6 alkyl, C1-C6 alkyl, perfluoro C1-C6 alkyl, fluoro, chloro, or any one of the following fragments:
(CH2)pxe2x80x94Oxe2x80x94(CH2)2N(R10)(R11) where R10 and R11 are as defined above, and p is 0 or 1;
xe2x80x94Oxe2x80x94(CH2)q- 
xe2x80x83where Q, together with the C atom to which it is joined, is a 5 or 6 membered heterocyclic ring (preferably saturated) containing one nitrogen atom, said heterocyclic ring being optionally substituted by C1-C4 alkyl, and q is 1 or 2;
xe2x80x94(CH2)rxe2x80x94C(R13)(R14)xe2x80x94(CH2)sxe2x80x94N(R15)(R16) where r and s are independently 0, 1 or 2 and R13 and R14 are independently hydrogen or C1-C4 alkyl optionally containing one oxygen atom in the chain or at the end of the chain, or R13 and R14 together with the carbon atom to which they are bonded for a 4 to 6 membered carbocyclic saturated ring;
R15 and R16 are independently selected from hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain, or R15 and R16 together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated heterocyclic ring;
or one of R13 or R14 and one of R15 or R16 together with the carbon and nitrogen atoms to which they are bonded form a 4 to 6 membered saturated heterocyclic ring in which case the other of R13 or R14 is hydrogen or C1-C4 alkyl, and the other of R15 or R16 is hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain;
or wherein R7xe2x80x94B represents any one of the following bicyclic fragments where R12 is as defined above 
with the proviso that R7, R8 and R9 cannot all be hydrogen, and only one of R7, R8 and R9 contains one nitrogen atom or, when R8 and R9 together form a ring, said ring contains only one nitrogen atom with the proviso that one of R8 or R9 may be the following fragment which contains two nitrogen atoms:
(the above proviso does not apply to the subject matter of the following paragraph) or,
B is a 4 to 7 membered saturated or partially saturated heterocyclic ring containing one or two heteroatoms wherein at least one is a nitrogen and the other is independently selected from oxygen, sulphur and nitrogen; and wherein R7 (when B is a saturated or partially saturated heterocycle) is one or more of C1-C6 alkyl or C3-C6 carbocyclic or C3-C6 carbocyclic C1-C4 alkyl, said carbocyclic containing zero one or more double bonds wherein said alkyl and carbocyclic optionally contain one heteratom selected from oxygen, sulphur and nitrogen (i.e. for alkyl the heteroatoms will be in the chain or at the end of the chain) and are further optionally substituted by one or more fluoro, or C1-C4 alkyl optionally containing an oxygen in the alkyl chain or at the end of the chain;
and pharmaceutically acceptable salts thereof.
Thus in accordance with the invention, the basic (nitrogen containing) centre can be located at various positions in formula 1 with the proviso that each compound of the invention should contain a single basic centre with a pKa (defined as the log of the ionisation constant of the corresponding conjugate acid) greater than 6 (such as 6.5).
In the above definition, unless otherwise indicated alkyl and alkoxy groups having three or more carbon atoms may be straight-chain or branched chain.
Herein C1-C4 alkyl or C1-C4 alkyl containing fragment means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; and C1-6 alkyl further includes the various straight and branched pentyl and hexyl fragments (although C1-C4 is preferred).
C3-C6 cycloalkyl (used hereinafter means cyclopropyl, cyclobutyl, cyclopenyl and cyclohexyl.
Herein C1-C6 alkyl optionally containing an oxygen atom in the chain or at the end of the chain includes moieties of the formula xe2x80x94(CH2)txe2x80x94Oxe2x80x94(CH2)uxe2x80x94CH3 where t is 1 to 5 and u is 0 to 4 and in C1-C4 alkyl of the same definition, t is 1, 2 or 3 and u is 0, 1 or 2.
The following independently represent preferred subclasses of the compounds of formula I.
R1 is hydrogen or methyl (most preferably hydrogen);
R2 is hydrogen or methyl;
R3 is hydrogen or methyl (most preferably hydrogen);
R4 is hydrogen.
R5 is hydrogen
R6 is C1-C6 alkyl (eg methyl), C3-C6 carbocylic optionally substituted by fluoro, or R5 and R6 together form a bridging chain containing 2 or 3 carbon atoms.
Y is hydrogen, chloro or bromo.
V is C
W is CH or N.
X is CH or N.
R10 and R11 independently represent hydrogen, C1-C4alkyl optionally containing an oxygen atom in the chain, or R10 and R11 together with the nitrogen to which they are bonded form a 5 to 6 membered heterocyclic ring wherein when the ring is six membered it may optionally contain one oxygen or a nitrogen atom present as N(R12).
R12 is hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain.
B is phenyl or a six membered aromatic heterocyclic ring containing one nitrogen atom, wherein said phenyl or heterocyclic ring may optionally be substituted by fluoro, chloro, C1-C4 alkyl or OC1-C4 alkyl.
Also in a preferred subclass of the compounds of formula(l), Bxe2x80x94Axe2x80x94 represents Bxe2x80x94CH2xe2x80x94C(R8)(R9)xe2x80x94(CH2)mN(R10)(R11), xe2x80x94CH2Oxe2x80x94(CH2)2N(R10)(R11), where R8 and R9 are independently hydrogen, or R8 and R9together form a 4 to 6 membered ring containing N(R12) m is 0, 1 and 2, and R10 and R11 are as defined above. More preferably, B is preferably phenyl when Bxe2x80x94A represents Bxe2x80x94CH2xe2x80x94(R8)(R9).
When C* is chiral in Bxe2x80x94CH2xe2x80x94C*(R8)(R9), then the S-enantiomer is preferred.
In a preferred subclass of compounds B is phenyl and R7 is xe2x80x94(CH2)rxe2x80x94C(R13)(R14)xe2x80x94(CH2)sxe2x80x94N(R15)(R16) wherein r, s, and R13 to R16 are as defined hereinbefore.
When B is phenyl, preferably R7 is connected at the 3 position of the phenyl ring (relative to connection to the xe2x80x98Axe2x80x99 moiety at position 1). A
In another preferred sub-class of compounds B is a saturated or partially saturated 4 to 7 membered heterocyclic ring containing one or two heteroatoms, at least one of which is nitrogen and the other is selected from oxygen, sulphur and nitrogen; and R7, is R17 which is substituted on the nitrogen of the heterocyclic ring and is selected from one or more of C1-C6 alkyl, C3-C6 carbocyclic or C3-C6 carbocyclic C1-C4 alkyl, said carbocyclic containing zero, one or more double bonds wherein said alkyl and carbocyclic optionally contain one heteroatom selected from oxygen, sulphur and nitrogen and are further optionally substituted by one or more fluoro atoms or C1-C4 alkyl optionally containing an oxygen in the alkyl chain or at the end of the chain. More preferably the saturated or partially saturated heterocycle is furthermore optionally substituted by R18 which is independently selected from one or more of C1-C6 alkyl, per fluoro C1-C6 alkyl wherein said alkyl optionally contains an oxygen atom in the chain or at the end of the chain. Still more preferably the heterocyclic ring is a 5 to 6 membered saturated heterocyclic ring, and Bxe2x80x94A is Bxe2x80x94C (R8)(R9) wherein R8 and R9 are as defined hereinbefore.
Preferably also, the heterocyclic ring is connected at the 2-position (i.e. adjacent the nitrogen) to the xe2x80x98Axe2x80x99 moiety.
Preferably C3-C8 carbocyclic and C3-C6 carbocyclic C1-C4 alkyl moiety of R17 is an optionally substituted C3-C6 cycloalkyl (such as cyclopentyl) or C3-C6 cycloalkyl C1-C4 alkyl, (such as cyclopropylmethyl). More preferably R17 is cyclopropylmethyl. More particularly, preferred radicals of R7xe2x80x94Bxe2x80x94A are:
and 
Examples of radicals (a) to (k) are shown below. 
(wherein the S-enantiomer is preferred for fragments (a) and (b)). 
Preferred compounds according to the invention are as follows:
(R,S)-2-[3-[(2-amino-1-benzylethyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]-N-(1H-indol-5-ylmethyl)acetamide;
2-[3-(3-[(dimethylamino)methyl]phenethylamino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-(1H-indol-5-ylmethyl)acetamide;
2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6H)-pyrazinyl]-N-(1H-indol-5-ylmethyl)acetamide;
2-[3-[(1S)-1-benzyl-2-(dimethylamino)ethyl]amino-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-(1H-indol-5-ylmethyl)acetamide;
2-[3-[(1S)1-benzyl-2-(dimethylamino)ethyl]amino-5chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-(1H-indol-5-ylmethyl)acetamide;
2-[3-{[(2R,S)-3-(dimethylamino)-2-phenylpropyl]amino}-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-(1H-indol-5-ylmethyl)acetamide;
N-[(3-Methyl-1H-indol-5-yl)methyl]-2-[6-methyl-3-([3-[(methylamino)methyl]phenethyl]amino)-2-oxo-1(2H)-pyrazinyl]acetamide;
2-[3-{[(1S)1-benzyl-2-(dimethylamino)ethyl]amino}-6-methyl-2oxo-1(2H)-pyrazinyl]-N-[(6-methyl-1H-indazol-5-yl)methyl]acetamide;
2-[3-{[3-(3-azetidinyl)phenethyl]amino}-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
N-[(3-methyl-1H-indol-5-yl)methyl]-2-[6-methyl-3-{[3-(1-methyl-3-azetidinyl)phenethyl]amino}-2-oxo-1(2H)-pyrazinyl]acetamide;
2-[3-[(3-{[(2-methoxyethyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
2-[3-({[(2R)-1-(cyclopropylmethyl)pyrrolidinyl]methyl}amino)-6-metbyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
2-[3-({[(2R)-1-cyclopentylpyrrolidinyl]methyi}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
N-[(3-methyl-1H-indol-5-yl)methy]-2-[6-methyl-2-oxo-3-({[(2R)-1-tetrahydro-2H-pyran-4-ylpyrrolidinyl]methyl}amino)-1(2H)-pyrazinyl]acetamide;
N-[(3-methyl-1H-indol-5-yl)methyl]-2-[6-methyl-3-[({(2R)-1-[(1-methylcyclopropyl)methyl]pyrrolidinyl}methyl)amino]-2-oxo-1(2H)-pyrazinyl]acetamide;
2-[3-({[(2R)-1-(2-methoxyethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
N-[(3-methyl-1H-indol-5-yl)methyl]-2-[6-methyl-3-({[(2R)-1-neopentylpyrrolidinyl]methyl}amino)-2-oxo-1(2H)-pyrazinyl]acetamide;
2-[3-({[(2R)-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
2-[3-({[(2R)-1-(2-methoxyethyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
2-[3-({[(2R)-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
2-[3-({[(2R)-1-(cyclopropylmethyl)piperidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
and pharmaceutically acceptable salts thereof.
Preferably the compounds of the invention are selected from:
2-[3-(3-[(dimethylamino)methyl]phenethylamino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-(1H-indol-5-ylmethyl)acetamide;
2-[3-[(1S)-1-benzyl-2-(dimethylamino)ethyl]amino-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-(1H-indol-5-ylmethyl)acetamide;
N-[(3-Methyl-1H-indol-5-yl)methyl]-2-[6-methyl-3-([3-[(methylamino)methyl]phenethyl]amino)-2-oxo-1(2H)-pyrazinyl]acetamide;
2-[3-[(3-{[(2-methoxyethyl)amino]methyl}phenethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
2-[3-({[(2R)-1-(cyclopropylmethyl)pyrrolidinyi]methyl}amino)-6-methyl-2oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
2-[3-({[(2R)-1-cyclopentylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5yl)methyl]acetamide;
2-[3-({[(2R)-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]-N-[(3-methyl-1H-indol-5-yl)methyl]acetamide;
and pharmaceutically acceptable salts thereof.
It will be appreciated that many compounds of formula (I) contain one or more asymmetric centres and will therefore exist in the form of optical isomers. The present invention also includes within its scope all such enantiomers and mixtures thereof, including racemic mixtures thereof. In addition all possible diastereomeric forms (individual diastereoisomers and mixtures thereof of compounds of formula I are included within the scope of the invention.
Thus, for example, when R8 and R9 are different, then C* of the following fragment.
Bxe2x80x94C*(R8)(R9)xe2x80x94, Bxe2x80x94CH2xe2x80x94C*(R8)(R9)xe2x80x94, Bxe2x80x94C*(R8)(R9)xe2x80x94CH2xe2x80x94, Bxe2x80x94CH2xe2x80x94C*(R8)(R9)xe2x80x94CH2xe2x80x94, Bxe2x80x94C(R8)(R9)xe2x80x94CH2xe2x80x94CH2xe2x80x94, and Bxe2x80x94CH2xe2x80x94CH2xe2x80x94C*(R8)(R9)
will form an asymmetric centre.
In compounds containing the fragment Bxe2x80x94C*(R8)(R9)xe2x80x94, the S-enantiomer has been found to be substantially more active than the R-enantiomer. In radicals (a) and (b), the S-enantiomer is preferred, in radicals (i) and (j) the R-enantiomer is preferred (wherein the chiral carbon is indicated by an asterix) while in radical (k) the S enantiomer is preferred.
A further aspect of the invention provides compounds of formula(Ixe2x88x9d): 
wherein:
R1 is hydrogen, C1-C4 alkyl, perfluoro C1-C4 alkyl, OC1-C4 alkyl, fluoro or chloro;
R2 is hydrogen, CH3, or CF3;
R3 is hydrogen, C1-C4 alkyl, perfluoro C1-C4alkyl, OC1-C4 alkyl, fluoro or chloro;
R4 is hydrogen or C1-C4 alkyl;
R5 is hydrogen or C1-C4 alkyl;
R6 is hydrogen, cyclopropyl, C1-C4 alkyl, perfluoro C1-C4 alkyl, fluoro or chloro;
or R5 and R6 together form a bridging chain containing 2 or 3 carbon atoms;
Y is hydrogen, chloro, fluoro, bromo, methyl or CF3;
W and X are independently CH, CF, CCl or N;
Bxe2x80x94Axe2x80x94 is any one of the following fragments:
Bxe2x80x94C(R8)(R9)xe2x80x94
Bxe2x80x94CH2xe2x80x94C(R8)(R9)xe2x80x94
Bxe2x80x94C(R8)(R9)xe2x80x94CH2xe2x80x94
Bxe2x80x94CH2xe2x80x94C(R8)(R9)xe2x80x94CH2xe2x80x94
Bxe2x80x94C(R8)(R9)xe2x80x94CH2xe2x80x94CH2xe2x80x94
Bxe2x80x94CH2xe2x80x94CH2xe2x80x94C(R8)(R9)xe2x80x94
wherein:
R8 and R9 are independently hydrogen, xe2x80x94(CH2)mN(R10)(R11), xe2x80x94CH2Oxe2x80x94(CH2)2N(R10)(R11), or R8 and R9 together form a 4 to 6 membered ring containing a nitrogen atom present as N(R12); and
m is 0, 1 and 2 (preferably m=1) except where A represents xe2x80x94C(R8)(R9)xe2x80x94 when m is 1 or 2;
R10 and R11 are independently selected from hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain;
or R10 and R11 together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated heterocyclic ring wherein when the ring is six membered it may optionally contain one oxygen atom or a nitrogen atom present as N(R12);
R12 is hydrogen or C1-C4 alkyl optionally containing an oxygen atojn in the chain or at the end of the chain;
B is phenyl or a 5 or 6 membered aromatic heterocyclic ring containing up to two heteroatoms independently selected from oxygen, sulphur and nitrogen;
R7 is one or more of hydrogen, C1-C4 alkyl, perfluoro C1-C4 alkyl, OC1-C4 alkyl, perfluoro OC1-C4 alkyl, fluoro, chloro, or any one of the following fragments:
xe2x80x94Oxe2x80x94(CH2)2N(R10)(R11) where R10 and R11 are as defined above xe2x80x94(CH2)rxe2x80x94C(R13)(R14)xe2x80x94(CH2)sxe2x80x94N(R15)(R16) where r and s are independently 0, 1 or 2 and R13 and R14 are independently hydrogen or C1-C4 alkyl, or R13 and R14 together with the carbon atom to which they are bonded form a 4 to 6 membered carbocyclic saturated ring;
R15 and R16 are independently selected from hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain, or together R15 and R16 together with the nitrogen atom to which they are bonded form a 4 to 6 membered saturated hetorocyclic ring;
or one of R13 or R14 and one of R15 or R16 together with the carbon and nitrogen atoms to which they are bonded form a 4 to 6 membered saturated heterocyclic ring in which case the other of R13 or R14 is hydrogen or C1-C4 alkyl, and the other of R15 or R16 is hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain;
or wherein R7xe2x80x94B represents any one of the following bicyclic fragments where R12 is as defined above 
xe2x80x83with the proviso that R7, R8 and R9 cannot all be hydrogen, and only one of R7, R8 and R9 contains one nitrogen atom or, when R8 and R9 together form a ring, said ring contains only one nitrogen atom with the proviso that one of R8 or R9 may be the following fragment which contains two nitrogen atoms: 
and pharmaceutically acceptable salts thereof.
Another aspect of the present invention provides processes for the preparation of compounds of the general formula (I), their pharmaceutically acceptable salts and acceptable solvates of either entity, as illustrated below. It will be appreciated by persons skilled in the art that, within the various processes described, the order of the synthetic steps employed may be varied and will depend, inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates, and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps. It will also be appreciated that various standard transformations within certain compounds of formula (I) will provide other compounds of formula (I); examples are reductive alkylations of N-unsubstituted and N-monosubstituted amines with an appropriate aldehyde.or ketone and dealkylation of N-methylamines by treatment with xcex1-chloroethylchloroformate followed by methanolysis.
Moreover, persons skilled in the art will be aware of variations of, and alternatives to, those processes described hereinafter in the Examples and Preparations section which allow the compounds defined by formula (I) to be obtained.
Accordingly in a further aspect of the present invention there is provided processes for preparing the compounds of general formula (I) and (1xe2x88x9d), and pharmaceutically acceptable salts thereof comprising:
(a) coupling of an acid of formula (II) 
with a heterocyclic amine of formula (III) 
(b) coupling a heterocycle of formula (XII) 
wherein Z is a suitable leaving group, such as halogen,
with an amine of formula (V)
R7xe2x80x94Bxe2x80x94Axe2x80x94NH2xe2x80x83xe2x80x83(V);
or
(c) coupling a heterocycle of formula (1c) 
with a carbonyl of formula (XXXVII)
R7xe2x80x94Bxe2x80x94A1xe2x80x94C(O)xe2x80x94R8xe2x80x83xe2x80x83(XXXVII);
xe2x80x83wherein A1 is C(R8)(R9),CH2C(R8)(R9) or C(R8)(R9)CH2 
in the presence of a reducing agent; and optionally converting into a pharmaceutically acceptable salt.
General Method A
Compounds of the general formula (Ia) (Scheme I) may be prepared by coupling of the acid (II) with the appropriate heterocyclic amine (III) (Scheme 1). The coupling may be achieved using conventional amide bond forming techniques, in particular any one of a number of amino acid coupling variations. For example, the acid (II) may be activated using a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochroride optionally in the presence of 1-hydroxybenzotriazole hydrate and or a catalyst such as 4-dimethylaminopyridine. Such couplings may be performed in a suitable solvent such as dichloromethane or N,N-dimethylacetamide, optionally in the presence of a tertiary amine such as N-methylmorpholire or N,Ndiisopropylamine at 0xc2x0 C.
Compounds of the general formula (II) may be prepared from compounds of the general formula (IV) by hydrolysis or hyrogenation of the carboxylic acid ester and dechlorination of the pyrazinone ring (where R17 is as an aryl moiety or an alkyl moiety susceptible to hydrolysis to form the corresponding carboxylic acid). This conversion may be achieved in a single step where the carboxylic acid ester is removed by catalytic hydrogenation (eg R17=benzyl). For example a compound of the general formula (II) can be obtained from a compound of the general formula (IV) where R17=benzyl by treatment with a catalytic quantity of Pearimans catalyst under an atmosphere of hydrogen (preferably 60 psi) in a suitable solvent such as methanol, at room temperature for 2 to 24 hours. Altematively a compound of the general formula (IV) may be subject to ester hydrolysis according to the plethora of methods currently available. For example treatment with lithium hydroxide or sodium hydroxide in a mixture of methanol, THF and water at room temperature. Subsequent reduction of the pyrazinone chlorine substituent may be carried out by treatment with a suitable active metal catalyst under an atmosphere of hydrogen for example: Pearlmans catalyst under an atmosphere of hydrogen as described above or by transfer hydrogenation methodology for example: treatment with ammonium formate in methanol, ethanol or isopropanol in the presence of a catalytic amount of palladium on carbon catalyst.
Compounds of the general formula (IV) may be prepared by treatment of compounds of the general formula (VI) with a primary amine (V) in a solvent such as ethyl acetate or THF at reflux for 6 to 24 hrs in the presence of a suitable tertiary amine base for example triethylamine or N,N-diisopropylethylamine.
Compounds of the general formula (VI) may be prepared from a suitable ester derivative of glycine (VIII) according to the method of Hoornaert (J. Het. Chem. 1983, 20, 919,). 
Compounds of the general formula (III) may be prepared by reduction of compounds of the general formula (IX) (Scheme 2). Such a reduction may be performed with a variety of reagents; for example, lithium aluminium hydride or hydrogen over Raney Nickel catalysis. Preferred conditions involve the use of Raney Nickel with methanol as solvent which contains 20% ammonia. The reaction is carried out at a temperature of up to 50xc2x0 C. in an autoclave charged with hydrogen at a pressure up to 50 bar. Compounds of the general formula (IX) where W=CH, V=C and R1xe2x95x90R2xe2x95x90R3=R4xe2x95x90H are commercially available whilst compounds of the general formula (IX) where W=N or CH, V=C or N, R1xe2x95x90R2xe2x95x90R4=H and R3=Me may be prepared from the precursor (X) according to the method of H. D. Porter and W. D Peterson, (Org Synthesis, Coll Vol III p660).
Compounds of the general formula (IX) where W=CH, V=C, R2xe2x95x90CH3 and R1xe2x95x90R3=R4=H may be prepared from commercially available 5-cyano-1H-indole by formylation at the 3-position according to the method of P. N. James and H. R. Snyder, (Org Synthesis Coll Vol IV, p539) followed by simultaneous reduction of the formyl and cyano groups using a suitable reducing agent such as lithium aluminium hydride in an aprotic solvent for example tetrahydrofuran or diethyl ether. 
General Method B
An alternative method of preparation of compounds of the general formula (Ia) (Scheme 3) involves dechlorination of compounds of the general formula (XI) by reduction. Typically this procedure may be performed by treatment with a suitable active metal catalyst under an atmosphere of hydrogen, for example, Pearlmans catalyst under an atmosphere of hydrogen as described above (General Method A); or by transfer hydrogenation methodology, for example; treatment with ammonium formate in methanol, ethanol or isopropanol in the presence of a catalytic amount of palladium on carbon catalyst (General Method A). In scheme 3, Y has been indicated as chloro as a preferred embodiment but it will be appreciated that the reaction scheme is applicable for other components of Y, and therefore as a general principle Y can be indicated generally in scheme 3. Furthermore the chloro leaving group (in position 3) in scheme 3, as a general principle can be indicated as a xe2x80x9cleaving groupxe2x80x9d (formula XII) such as a halogen.
Compounds of the general formula (XI) may be prepared by treatment of compounds of the general formula (XIIA) with a primary amine of the general formula (V) according to the conditions described above in General Method A. Compounds of the general formula (XIIA) may be prepared from the carboxylic acid (XIII) and a suitable amine of the general formula (III) according to the general methods described above (General Method A). Compound (XIII) may be prepared from a compound of the general formula (VI) according to the plethora of methods. for the hydrolysis of a carboxylic acid ester (General Method A). 
Amines of the general formula (V) may be prepared from a variety of precursors. Preferred routes include preparation from the corresponding nitrile such as illustrated by formula (XIV) (Scheme 4). Preparation of the amines (Va) from the nitrites (XIV) may be achieved by reduction of the appropriate nitriles using Raney nickel under an atmosphere of hydrogen. Compounds of the general formula (XIV) may be prepared from compounds of the general formula (XV) by palladium catalysed functionalisation of the halo substituent preferably a bromo substituent (shown for convenience). For example, treatment of compound (XV) wiith a palladium catalyst (palladium acetate or tris triphenyphosphinepalladium) in the presence of sodium formate under an atmosphere of carbon monoxide gives compound (XIV) where R7=CHO. Subsequent treatment with a primary or secondary amine in the presence of a suitable reducing agent (e.g. sodium triacetoxyborohydride) in a protic solvent system (e.g. acetic acid, methanol) gives a compound of the general formula (XIV) where R7=CH2NR15R16. Alternatively the reaction may be carried out under conventional catalytic hydrogenation conditions. This synthetic methodology allows the preparation of preferred compounds of type (d). In a related methodology palladium catalysed cross coupling of (XV) with the zincate derived from N-Boc-3-iodoazetidine, by direct analogy to the procedure of S. Billotte, (Synlett, 1998, p379), gives a compound of the general formula (XIV) where R7=N-BOC-azetidine-3-yl. Deprotection of the nitrogen using standard methodology such as protonolysis using trifluoroacetic acid or hydrogen chloride and, if required, subsequent reductive alkylation with an appropriate aldehyde or ketone allows the preparation of preferred compounds of type (g). In the case of an aldehyde or ketone precursor the reaction may be carried out in the presence of a suitable reducing agent (e.g. sodium triacetoxyborohydride) in a protic solvent system (e.g. acetic acidi, methanol). Alternatively the reaction may be carried out under conventional catalytic hydrogenation conditions. Intermediate (XV) can be transmetalated with an appropriate organolithium such as butyllithium and reacted in situ with an N-substituted 2-pyrrolidone and the resulting intermediate (XIV) with R7=an N-substituted-2-hydroxypyrrolidin-2-yl fragment may be reduced directly using for example platinum oxide under an atmosphere of hydrogen, by direct analogy with the synthetic methodology of H. Malmberg, M. Nilllsson and C. Ullenius, (Acta Chemica Scandinavia, B, 35, 1981, p625), to allow the preparation of intermediate (Va) with R7=an N-substituted pyrrolidine-2-yl fragment. This synthetic methodology allows the preparation of preferred compounds of type (G). 
Amines of the general formula (Vb) may be prepared from a variety of precursors. Preferred routes include preparation from amino acid derivatives (XVI) (Scheme 5) and from the nitrile derivatives (XIV). Preparation from the amino acid derivatives (XVI) where P is a suitable protecting group for an amine (preferably BOC), may be achieved by reduction of the amide bond using lithium aluminium hydride, borane or lithium borohydride in the presence of trimethylsilyl chloride in an aprotic solvent such as diethyl ether or tetrahydrofuran. Subsequent removal of the nitrogen protecting group may be achieved using trifluoroacetic acid in dichloromethane or dichloromethane saturated with HCl. Amides of the general formula (XVI) may be prepared by coupling of the appropriate amine HNR10R11 with the commercially available amino acid derivatives (XVII). The coupling may be achieved using conventional amide bond forming techniques, in particular any one of a number of amino acid coupling variations described under General Method A. This synthetic methodology allows the preparation of preferred compounds of type (a). 
Amines of the general formula (Vc) (Scheme 6) may be prepared by treatment of compounds of the general formula (XVIII) where P is a suitable nitrogen protecting group (preferably BOC) with, for example, bromoacetonitrile and a suitable base in an aprotic polar solvent such as tetrahydrofuran, followed by reduction of the nitrile and removal of the nitrogen protecting group using, for example, ether saturated with HCl or trifluoroacetic acid in dichloromethane. Compounds of the general formula (XVIII) are commercially available. This synthetic methodology allows preparation of preferred compounds of the type (b). 
Amines of the general formula (Vd) (Scheme 7) may be prepared from intermediates of the general formula (XIX) by reduction according to the methods described above. Compounds of the general formula (XIX) may be prepared from compounds of the general formula (XX) by reaction of compounds of the general formula (XX) with sodium cyanide in suitable solvent for example, tetrahydrofuran or acetonitrile. Compounds of the general formula (XX) may be prepared from compounds of the general formula (XXI) by bromination using for example, N-bromosuccinimide as reviewed by L. Horner and E. H. Winkelmann in Angewandte Chemie 1959, 71, 349. Intermediates (XXI) may be prepared from compounds of the general formula (XXII) by nucleophilic attack onto the carbon atom of the cyano group according to the method of Ciganeck (J. Org. Chem. 1992, 57, 4521) or the method of Calderwood, (Tetrahedron Letters, 1997, 38, 1241). This synthetic methodolgy allows the preparation of preferred compounds of the type (d). 
Amines of the general formula (Ve) (Scheme 8) may be prepared by reduction of the commercially available nitrile (XXIII) using the method of F. Vogtle et al (Chem Ber, 1984, 117, 1487). One of the amines in intermediate (XXIV) may be protected with a suitable protecting group P (preferably BOC) using the method of Adamczyk et al; (Org Prep Proc Int, 1998, 30(3) 339) or the method of Krapcho et al, (Syn Comm, 1990, 20, 2559) to give compounds of the general structure (XXV). Reductive amination of the unprotected primary amine of compounds of the formula (XXV) and subsequent removal of the protecting group P gives compounds of the general formula (Ve). This synthetic methodology allows the preparation of preferred compounds of type (e). 
Amines of the general formula (Vf) (Scheme 9) may be prepared from intermediates of the general formula (XXVI) by reduction of the nitrile group using for example, Raney nickel in ethanol saturated with ammonia. Compounds of the general formula (XXVI) may be prepared from compounds of the general formula (XXVII) by removal of the nitrogen protecting group P and subsequent reductive amination. Compounds of the general formula (XXVII) can be prepared by alkylabon of the phenol (XXVIII) (or hydroxy methyl phenyl) with a suitably protected alcohol (XXIX) according to the method of O. Mitsonubu, (Synthesis, 1981,1). Compound (XXVIII) is prepared from commercially available (XXX) by demethylation using for example, a solution of boron tribromide in dichloromethane. This methodology is also applicable for compounds where there is a methylene between the benzene and oxygen, such as shown in the accompanying examples 27 and 28. This said methodology allows the preparation of preferred compounds of the general type (h). 
Amines of the general formula (Vg) (Scheme 10 and Scheme 11) may be prepared according to the method described by J. Permattam et al (Tett, Let, 1991, 32, p7183). For example, commercially available D-prolinamide (XXXI) can be treated with an aldehyde in the presence of a suitable reducing agent (eg sodium triacetoxyborohydride) in a protic solvent system (eg acetic acid or methanol) or by alkylation with a suitable alkylating agent as described by J. Permattam et al (Tett, Let, 1991, 32, p7183) to give a compound of formula (XXXII). Subsequent reduction of the amide with a suitable reducing agent (for example lithium aluminium hydride) in a suitable aprotic solvent (for example, diethyl ether or tetrahydrofuran) as described by J. Permattam et al (Tett, Let, 1991, 32, p7183) gives a compound of the general formula Vg. This synthetic methodology allows the synthesis of preferred compounds of type (i) and (j). 
Preferred compounds of the type (k) may be made according to the general method described in Scheme 11. Carboxylic acid (XXXIII) may be prepared according to the method described by G. R. Brown et. Al. in J. Chem. Soc. Perkin Trans I, 1985, 2577. Subsequent formation of the primary amide (XXXIV) may be performed using a suitable carboxylic acid activating agent (for example oxalyl chloride) in a suitable solvent system (for example, dichloromethane with a trace of dimethyl formamide). Reduction of (XXXIV) using a suitable reducing agent (for example lithium aluminium hydride) in a suitable aprotic solvent (for example diethyl ether or tetrahydrofuran) provides compounds of the type (k). 
General Method C
As a general principle, pyridone derivatives of formula (I)xe2x80x94i.e. formula (1b) in scheme 12, can be formed by coupling the heterocycle of formula (1c) with a carbonyl of formula (XXXVII) in the presence of a reducing agent (see hereinbefore). Compounds of the general formula (Ib) may also be prepared by coupling of the acid (XXXV) with the appropriate heterocyclic amine (III) (Scheme 12). The coupling may be achieved using conventional amide bond forming techniques, in particular any one of a number of amino acid coupling variations. For example, the acid (XXXV) may be activated using a carbodiimide such as 1-ethyl-3-(3-dimethylamino-1-propyl)carbodiimide optionally in the presence of 1-hydroxybenzotriazole and or a catalyst such as 4-dimethylaminopyridine. Such couplings may be performed in a suitable solvent such as dichloromethane, optionally in the presence of a tertiary amine such as N-methylmorpholine or N,N-diisopropylamine at 0xc2x0 C.
Compounds of the general formula (XXXV) may be prepared from compounds of the general formula (XXXVI) where P is a suitable carboxylic acid protecting group (preferably P is the tert-butyl group) by hydrolysis of the carboxylic acid ester using, for example if P=tert-butyl, trifluoroacetic acid in a suitable solvent such as dichloromethane at, for example, a temperature between 0xc2x0 C. and room temperature.
Compounds of the general formula (XXXVI) may be prepared by the reaction of the amine (XXXVIII) with the desired carbonyl compound (XXXVII) in the presence of a suitable reducing agent. Preferred conditions involve the use of sodium triacetoxyborohydride in tetrahydrofuran and acetic acid.
Compound (XXXVIII) may be prepared from the carbamate (XXXIX) by removal of the carbamate protecting group using a suitable catalyst under an atmosphere of hydrogen. Typical conditions involve the use of 10% palladium on carbon, at room temperature in ethyl acetate under a hydrogen pressure of 2 to 20 psi.
Compound (XXXIX) may be prepared by alkylation of compound (XXXX) using a suitably protected haloacetic acid derivative (XXXXI) where P is the acid protecting group (preferably P=tert-butyl) and a suitable base, for example potassium carbonate, sodium carbonate, caesium carbonate, sodium hydride or potassium hydride in a polar solvent such as acetone, THF, dimethyl formamide or 2-butanone. Preferred conditions involve the use of potassium carbonate in 2-butanone at room temperature.
Compound (XXXXI) is prepared from commercially available (XXXXII) following the procedure described for a closely related compound by D. J. Wolanin and C. A. Veale et al, (J. Med Chem 1994, 37, 3303). 
Carbonyl compounds of the general formula (XXXVII) may be prepared by oxidation of alcohols of the general formula (XXXXIII) where A1 is C(R8)(R9), CH2C(R8)(R9), or C(R8)(R9)CH2, (Scheme 13). Such an oxidation may be performed by a variety of agents known to oxidise an alcohol including CrO3/H2SO4 in acetone (Jones Reagent), CrO3Pyr2 (Collins Reagent), MnO2 or the methods of Swem or Dess-Martin. A preferred method is that of Swem involving the use of dry DMSO and oxalyl chloride in dichloromethane as solvent at xe2x88x9260xc2x0 C. under a nitrogen atmosphere. 
General Method D
Compounds of the general formula (XXXVII) may also be prepared from compounds of the general formula (XXXVIII) by treatment with a suitable triflate of the general formula (XXXXIV) in the presence of a base; for example pyridine, triethylamine or N-ethyl-diisopropylamine in a non protic solvent such as dichloromethane, THF or diethyl ether (scheme 14). Preferred conditions for this reaction involve the use of N-ethyl-diisopropylamine as the base in dichloromethane. 
Triflates of the general formula (XXXXIV) may be prepared from alcohols of the general formula (XXXXV) by treatment with trifluoromethanesulfonic anhydride in the presence of a suitable base; for example pyridine, triethylamine or N-ethyl-diisopropylamine in a non protic solvent such as dichloromethane, THF or diethyl ether. Preferred conditions include the use of trifluoromethane sulfonic anhydride in dichloromethane with pyridine as the solvent at 0xc2x0 C. to room temperature (scheme Scheme 15). 
Preperation of compounds of the type of example 24 (i.e. wherein the pyrollidine is attached at the 3-position to the methyl amino moiety), can be prepared according to scheme 16.
Amines of the general formula (XXXXVIII) may be made according to the general method described in scheme 16. The mesylate (XXXXVI) may be prepared in a 2-step procedure from (3R)-pyrrolidinol, by suitable protection of the amine (preferably Boc), following such methods as described in xe2x80x9cProtective groups in Organic synthesisxe2x80x9d, by T W Greene and P G M Wutz (1991) or xe2x80x9cProtecting Groupsxe2x80x9d by P J Kocienski (1994), followed by mesylation of the intermediate alcohol. The alcohol is treated with methanesulphonyl chloride in the presence of a suitable base, such as triethylamine or pyridine, in a non protic solvent such as dichloromethane, at between 0xc2x0 to room temperature. Amines of general formula (XXXXVII) may be prepared by reaction of compounds of formula (XXXXVI) with potassium cyanide in a suitable high boiling solvent, preferably DMSO, at between room temperature and 100xc2x0 C. Amines of general formula (XXXXVIII) may be obtained from the nitrile of formula (XXXXVII) by reduction using Raney(copyright) nickel in an alcoholic solvent, (e.g. methanol), under an atmosphere of hydrogen. 
This following synthetic methodology allows the preparation of preferred compounds of the type analogous to example 29.
Palladium catalysed cross coupling of (XV) with vinyl tributyl tin, by analogy with methods described in (Org. React. 1997; 50) gave the vinyl acetonitrile, and subsequently the vinyl amine (XXXXIX), by employing a selective reducing agent (e.g. AlCl3/LiAlH4) in a non protic solvent (e.g. tetrahydrofuran). Protection of the amine with a suitable protecting group (preferably CBz) following methods described in xe2x80x9cProtective groups in Organic synthesisxe2x80x9d, by T W Greene and P G M Wutz (1991) or xe2x80x9cProtecting Groupsxe2x80x9d by P J Kocienski (1994), followed by asymmetric aminohydroxylation (AA), according to the method of O""Brien et al (J. Chem. Soc. Perk. Trans. 1, 1998, 2519) provided the hydroxyamine of general formula (LI). Subsequent methylation, using an alkylating agent (eg methyl iodide), under phase transfer conditions, using a catalyst such as benzyltriethylammonium chloride, provided the compound of general formula (LII)
Removal of the initial nitrogen protecting group may be achieved by, for example, hydrogenation in the presence of a palladium on carbon catalyst in methanol, at a pressure of, typically 15 psi.
Compounds of formula (I) and the various intermediates and reagents required for the processes hereinbefore disclosed, when neither commercially available nor subsequently described, can be obtained either by analogy with the reactions described in the Examples and Preparations sections or by conventional synthetic procedures, in accordance with standard textbooks on organic chemistry or literature precedent, from readily accessible starting materials using appropriate reagents and reaction conditions.
The novel intermediates described herein form a further aspect of the invention. Where keto/enol tautomerism is present the keto and enol forms are claimed separately and together (as a mixture).
Suitable pharmaceutical and physiologically acceptable salts will be apparant to those skilled in the art and include for example acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or napthalenesulphonic acid. Other non-physiologically acceptable salts e.g. oxalates may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
The acid addition salts of the compounds of formula (I) may be prepared in a conventional manner. For example a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt isolated either by filtration or by evaporation under reduced pressure of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula (I) with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
The subject invention also includes pharmaceutially acceptable solvates (including hydrates), and polymorphs of the compounds of the invention. It will be further appreciated that certain moieties known as xe2x80x9cpro-moietiesxe2x80x9d, for example as described in xe2x80x9cDesign of Prodrugsxe2x80x9d by H. Bundgaard, Elsevier, 1985 (the disclosured of which is hereby incorporated by reference), may be placed on appropriate functionalities of the compounds of formula 1. Such prodrugs are included within the scope of the invention.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention and pharmaceutically acceptable salts of said compounds or which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
In therapy, the compounds of formula (I), their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity, can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Preferably, they are administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. They can also be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous lo solution which may contain other substances, for example enough salts or glucose to make the solution isotonic with blood. For buccal or sublingual administration they may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
For oral, parenteral, buccal and sublingual administration to patients, the daily dosage level of the compounds of formula (I) and their pharmaceutically acceptable salts and solvates may contain from 1 to 1000 mg (in single or divided doses). Thus tablets or capsules may contain from 0.5 to 500 mg of active compound for administration singly, or two or more at a time, as appropriate.
The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.